Neural stem cell plasticity

Group leader : C. Maurange

Our team investigates the molecular principles underlying modulations of neural stem cell properties during the different phases of brain building thus ensuring that all types of neurons are produced. We are also exploring the impact of suboptimal nutritional on neural stem cells, and are studying how neural stem cell properties may be hijacked during the cancerous process.

FOR BEGINNERS

Neural stem cells found in the brain and nervous system are very plastic. This plasticity allows each one of them to generate a vast repertoire of neural and glial progeny while the brain is being built during foetal life or to regenerate neurons after brain injury. However, the mechanisms underlying this plasticity remain unclear. Our team aims at deciphering the molecular and genetic mechanisms involved. We are also trying to investigate how environmental conditions during foetal growth affect neural stem cell plasticity and their ability to constitute their full repertoire of neurons. Finally, because of their plasticity and large proliferation potential, stem cells are largely exposed to cancer-promoting defects. Our ambition therefore consists in uncovering how neural stem cell plasticity can be hijacked for the benefit of cancerous processes.

In order to investigate these fascinating issues, we use the fruitfly Drosophila. Work on this insect over the last 100 years has allowed for major discoveries in all fields of biology and medicine, culminating in several Nobel prizes. Indeed, many of the genes and molecular principles allowing an organism to develop from an egg have been conserved in species throughout evolution. The Drosophila adult brain, as in mammals, is mainly composed of neurons and glial cells (more than 100000) disposed in complex neural circuits. These cells have been generated in the developing animal from a limited set of progenitors called neural stem cells. We take advantage of the powerful genetic tools developed in this model organism to manipulate neural stem cells while the brain is being constructed during development. We aim at identifying the genes and molecular mechanisms controlling their properties.

We try to decipher how a genetic program, governed by a series of sequentially expressed transcription factors, known as the temporal series, is deployed in every neural stem cells to ensure that different types of neurons are generated over time. This involves transcriptomic and epigenetic studies that will help identifying genes which temporally-regulated expression controls neural stem cell proliferation and differentiation properties.

Confocal section through the optic lobes in the brain of two adult Drosophila raised under different nutritional conditions. Undernourished flies exhibit a smaller optic lobe with fewer neurons (DNA in white). Yet, the image reveals that the structure of the brain is preserved (dendrites labelled in red) showing that the diversity of neurons and the proportions between the different subtypes are protected.

We investigate the impact of nutritional conditions on the making of the brain. We have recently identified an adaptive strategy used by the developing brain to modulate its size according to nutritional conditions. This system allows the brain to reduce the number of neurons while preserving neuronal diversity during nutrient restriction. We are currently dissecting the mechanisms underlying this brain-sparing strategy.

Drosophila larval nervous system in which tumors (red) deriving from neural stem cells (blue) have been induced, and are followed over the cancerisation process.

We explore the mechanisms that drive tumor progression in the Drosophila brain. Neural stem cells have the ability to divide asymmetrically. By this way, they self-renew while budding-off progeny that differentiate in neurons or glia. Some mutations perturb this division mode leading to an amplification of neural stem cell numbers at the expense of neurons. Interestingly, these supernumerary stem cells rapidly acquire cancerous properties escaping all proliferation control mechanisms. Yet the underlying process is unknown. We have devised a genetic assay that allows us to track and genetically manipulate neural stem cell-derived tumours during the different steps of cancer progression. Using this assay, we are investigating the molecular events driving cancer transformation in these neural tumours. These studies might open new avenues for the identification of novel therapeutic targets aiming at eliminating cancer stem cells that remain particularly resistant to current treatments.

Selected publications

PUBLICATION

March 6th, 2019

Developmental regulation of regenerative potential in Drosophila by ecdysone through a bistable loop of ZBTB transcription factors

Cassandra Gaultier

Saida Nait Amer

Karine Narbonne-reveau

Researcher

Karine joined CNRS as a researcher after a post-doc at the NIH in the United States. She joined the team in 2011. She is interested in understanding how defects in differentiation induce the emergence of cancer neural stem cells.